The objective of the proposed research is to understand the implications of densely ionizing radiations emitted by diagnostic and therapeutic radionuclides (Auger electrons and alpha particles) for both radiation protection and cancer therapy. We plan to elucidate the radiation biophysics of these short-range, high-LET particles and to use the information in studies of various radiobiologic effects and in experimental therapeutics. To this end, we propose to examine the microscopic distribution of damage in well-characterized and relatively simple systems (e.g. oligonucleotides, plasmids) in response to spatial positioning of the decaying nuclide and to changes in the surrounding environment. In addition, we will utilize individual cells as test systems for determining the quantitative relationships between microscopic dose and detrimental biologic effects by (i) exploring the molecular consequences of noncovalent DNA binding of Auger-electron emitting radiohalides as expressed by DNA strand breaks; and (ii) determining the radiotoxicity and mutagenic effects of the diagnostic radionuclides 99mTC and 111In when they are concentrated by cells and relating the results to the microscopic distribution of their conversion electrons. Studies will be repeated in the presence of radical scavengers to explore the role of hydroxyl radicals in these processes. In addition, we plan to continue our studies of cytotoxicity mutagenesis, and cellular transformation following the decay of the alpha particle emitters 211At and 212Bi when localized extra-cellularly, on plasma membranes, and intranuclearly. We will also exploit animal tumor models as pre-clinical systems for determining the utility of these agents in therapy and for establishing preliminary time-dose relationships. These models will include closed systems (brain, spinal cord, peritoneum) for the introduction of radiopharmaceuticals and one system accessible by differential perfusion (liver). Finally, in an attempt to extend the utility of radionuclide particle therapy, we plan to initiate combined modality experiments with photons plus alpha particle or Auger electron emitters.